Figure 5.

Roles of transforming growth factor β (TGF-β) and bone morphogenetic protein (BMP) signaling in bone homeostasis. Bone homeostasis is maintained through continuous cycles of bone resorption by osteoclasts and new bone formation by osteoblasts and osteocytes. Both TGF-β and BMP signaling participate in regulating this process. TGF-β can act as a chemoattractant and recruit both preosteoblast and preosteoclasts to areas of bone remodeling and also promotes proliferation, differentiation, and survival of osteoclasts. At low doses, TGF-β increases secretion of RANKL (receptor activator of NF-κB ligand) and suppresses expression of the inhibitor OPG (osteoprotegerin), thus promoting osteoclastogenesis by activating RANK signaling in preosteoclasts. At high doses, it suppresses RANKL and increases OPG expression and thus inhibits osteoclastogenesis. This biphasic effect limits excessive bone degradation in the presence of high levels of active TGF-β derived from conversion of latent TGF-β by proteases and acid secreted by osteoclasts during bone degradation. BMP signaling suppresses osteoclast differentiation by increasing expression of OPG in osteoblasts. It can, however, also promote bone resorption by increasing the expression of sclerostin (SOST), an inhibitor of Wnt signaling which is a pathway that normally promotes osteoblastogenesis and bone formation. M-CSF, Macrophage-colony stimulating factor.